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• Therapeutic strategy is very limited for severe infections with New Delhi metallo-β-lactamase (NDM)-producing organisms. • In vitro efficacy of meropenem (MEM) and cefmetazole (CMZ) combination assessed against NDM-producing Enterobacteriaceae. • Synergistic effect of MEM/CMZ for all tested isolates of NDM-producing Enterobacteriaceae: 2- to 8-fold MIC reduction of MEM. • Kinetic studies indicated CMZ may be an antagonist for NDM-1. • In vitro studies showed the potential effectiveness of MEM/CMZ combination therapy against NDM-producing organisms. Limited treatment options complicate management of infections with New Delhi metallo-β-lactamase (NDM)-producing organisms. The efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) was assessed against NDM-producing Enterobacteriaceae. Twelve Escherichia coli clinical isolates harbouring bla NDM-1 and a positive control E. coli BAA-2469 harbouring bla NDM-1 were studied. Minimum inhibitory concentrations (MICs) of MEM, ertapenem (ERT) and CMZ were determined by broth microdilution. Checkerboard and time-kill assays were performed to confirm the in vitro efficacy of the MEM/CMZ combination. Scanning electron microscopy, kinetic studies and whole-genome sequence analysis were used to determine the antimicrobial resistance mechanisms. MICs of MEM, ERT and CMZ in monotherapy ranged from 8 to 32, 16 to 128, and 32 to 512 µg/mL, respectively. In the checkerboard assay, MEM/ERT resulted in no synergy, whereas MEM/CMZ showed a synergistic effect in all the tested isolates. Furthermore, the MIC of MEM in combination decreased by 2- to 8-fold compared with that of MEM alone. The time-kill study revealed a bactericidal effect in 4 of 13 isolates at 24 h. Scanning electron microscopy showed spheroidisation of the bacterial cell in the MEM/CMZ combination; this was not observed in single antibiotic conditions. Kinetic studies indicated CMZ was a better antagonist for NDM-1 than ERT. Whole-genome sequence analysis did not reveal any explainable differences between isolates susceptible and those non-susceptible to combination therapy. In vitro studies showed the potential effectiveness of MEM/CMZ combination therapy against NDM-producing organisms. [ABSTRACT FROM AUTHOR]